Substituted imidazole derivatives and methods of use thereof

ABSTRACT

The present invention provides intermediates for methods for synthesizing compounds of Formula (I) and pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION

This invention relates to compounds which are inhibitors of theinteraction between the receptor for advanced glycation endproducts(RAGE) and its physiological ligands such as advanced glycated endproducts (AGEs), S100/calgranulin/EN-RAGE, β-amyloid, and amphoterin,for the treatment of RAGE mediated diseases.

BACKGROUND OF THE INVENTION

The Receptor for Advanced Glycated Endproducts (RAGE) is a member of theimmunoglobulin super family of cell surface molecules. The extracellular(N-terminal) domain of RAGE includes three immunoglobulin-type regions,one V (variable) type domain followed by two C-type (constant) domains(Neeper et al., J. Biol. Chem. 267:14998-15004 (1992)). A singletransmembrane spanning domain and a short, highly charged cytosolic tailfollow the extracellular domain. The N-terminal, extracellular domaincan be isolated by proteolysis of RAGE to generate soluble RAGE (sRAGE)comprised of the V and C domains.

RAGE is expressed in most tissues, and in particular, is found incortical neurons during embryogenesis (Hori et al. (1995)). Increasedlevels of RAGE are also found in aging tissues (Schleicher et al., J.Clin. Invest. 99 (3): 457-468 (1997)), and the diabetic retina,vasculature and kidney (Schmidt et al., Nature Med. 1:1002-1004 (1995)).Activation of RAGE in different tissues and organs leads to a number ofpathophysiological consequences. RAGE has been implicated in a varietyof conditions including: acute and chronic inflammation (Hofmann et al.,Cell 97:889-901 (1999)), the development of diabetic late complicationssuch as increased vascular permeability (Wautier et al., J. Clin.Invest. 97:238-243 (1996)), nephropathy (Teillet et al., J. Am. Soc.Nephrol. 11:1488-1497 (2000)), atherosclerosis (Vlassara et. al., TheFinnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), andretinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE hasalso been implicated in Alzheimer's disease (Yan et al., Nature 382:685-691 (1996)), erectile dysfunction, and in tumor invasion andmetastasis (Taguchi et al., Nature 405: 354-357 (2000)).

Advanced glycation endproducts (AGEs) have been implicated in a varietyof disorders including complications associated with diabetes and normalaging. Incubation of proteins or lipids with aldose sugars results innonenzymatic glycation and oxidation of amino groups on proteins to formAmadori adducts. Over time, the adducts undergo additionalrearrangements, dehydrations, and cross-linking with other proteins toform complexes known as AGEs. Factors which promote formation of AGEsinclude delayed protein turnover (e.g. as in amyloidoses), accumulationof macromolecules having high lysine content, and high blood glucoselevels (e.g. as in diabetes) (Hori et al., J. Biol. Chem. 270:25752-761, (1995)).

AGEs display specific and saturable binding to cell surface receptors onendothelial cells of the microvasculature, monocytes and macrophages,smooth muscle cells, mesengial cells, and neurons.

In addition to AGEs, other compounds can bind to, and inhibit theinteraction of physiological ligands with RAGE. In normal development,RAGE interacts with amphoterin, a polypeptide which mediates neuriteoutgrowth in cultured embryonic neurons (Hori et al., (1995)). RAGE hasalso been shown to interact with EN-RAGE, a protein having substantialsimilarity to calgranulin (Hofmann et al. (1999)). RAGE has also beenshown to interact with β-amyloid (Yan et al., Nature 389:689-695 (1997);Yan et al., Nature 382:685-691 (1996); Yan et al., Proc. Natl. Acad.Sci., 94:5296-5301 (1997)).

Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE, β-amyloid,CML (Nε-Carboxymethyl lysine), and amphoterin to RAGE has been shown tomodify expression of a variety of genes. For example, in many cell typesinteraction between RAGE and its ligands generates oxidative stress,which thereby results in activation of the free radical sensitivetranscription factor NF-κB, and the activation of NF-κB regulated genes,such as the cytokines IL-1β, TNF-α, and the like.

In addition, several other regulatory pathways, such as those involvingp21ras, MAP kinases, ERK1 and ERK2, have been shown to be activated bybinding of AGEs and other ligands to RAGE. In fact, transcription ofRAGE itself is regulated at least in part by NF-κB. Thus, an ascending,and often detrimental, spiral is fueled by a positive feedback loopinitiated by ligand binding. Inhibiting binding of physiological ligandsto RAGE provides for the down-regulation of the pathophysiologicalchanges brought about by excessive concentrations of AGEs and otherligands for RAGE as described above.

Thus, there is a need for the development of compounds that inhibit thebinding of physiological ligands to RAGE.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein

-   R¹ and R² are independently selected from the group consisting of    —CH₃, —CH₂CH₃, —CH(CH₃)₂, and —CH₂CH₂CH₃; and-   Q¹ is selected from the group consisting of —CH₂OCH₂CH₃ and    —CH₂CH₂CH₂CH₃.

This invention also provides for methods of preparation of compounds ofFormula (I) or pharmaceutically acceptable salts thereof, pharmaceuticalcompositions comprising compounds of Formula (I) or pharmaceuticallyacceptable salts thereof; and methods for the use of compounds ofFormula (I) or pharmaceutically acceptable salts thereof in treatingdiseases mediated by RAGE.

Compounds of Formula (I) or pharmaceutically acceptable salts thereofare useful as inhibitors of the interaction of the receptor for advancedglycation endproducts (RAGE) with ligands such as advanced glycated endproducts (AGEs), S100/calgranulin/EN-RAGE, β-amyloid, and amphoterin.The compounds are also useful in treating a variety of diseases orconditions in humans that may be responsive to the inhibition of RAGE.Such diseases or conditions include, but are not limited to, acute andchronic inflammation, the development of diabetic late complicationssuch as increased vascular permeability, nephropathy, atherosclerosis,and retinopathy, the development of Alzheimer's disease and relateddisorders, erectile dysfunction, tumor invasion and metastasis, andosteoporosis.

The scope of the present invention includes combinations of the variousaspects, embodiments, and preferences as herein described.

BRIEF DESCRIPTION OF DRAWINGS

Not applicable

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are meant to clarify, but not limit, the termsdefined. If a particular term used herein is not specifically defined,such term should not be considered indefinite. Rather, such terms areused within their plain and ordinary meanings.

As used herein, the various functional groups represented will beunderstood to have a point of attachment at the functional group havingthe hyphen. In other words, in the case of —CH₂CH₂CH₃, it will beunderstood that the point of attachment is the CH₂ group at the farleft.

In a first embodiment, the present invention includes a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ and R² are independently selected from the group consisting of —CH₃,—CH₂CH₃, —CH(CH₃)₂, and —CH₂CH₂CH₃; and

Q¹ is selected from the group consisting of —CH₂OCH₂CH₃ and—CH₂CH₂CH₂CH₃.

In a second embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof wherein R¹ is—CH₃.

In a third embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof wherein R¹ is—CH₂CH₃.

In a fourth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the previous embodiments wherein R² is —CH₃.

In a fifth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to third embodiments wherein R² is —CH₂CH₃.

In a sixth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the previous embodiments wherein Q¹ is —CH₂OCH₂CH₃.

In a seventh embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to fifth embodiments wherein Q¹ is —CH₂CH₂CH₂CH₃.

In an eighth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to seventh embodiments wherein the compound is afree amine.

In a ninth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to seventh embodiments wherein the compound is apharmaceutically acceptable salt.

In a tenth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to seventh embodiments wherein the compound is ahydrochloride salt.

In an eleventh embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to tenth embodiments wherein the group—CH₂CH(OH)CH₂NR¹R² is in the S configuration.

In a twelfth embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof according toany one of the first to tenth embodiments wherein the group—CH₂—CH(OH)—CH₂—NR¹R² is in the R configuration.

Specific embodiments of the compound of Formula (I) or apharmaceutically acceptable salt thereof include:

-   (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol;-   (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol;-   (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol;-   (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol;-   (R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol;-   (S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol;-   (R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol;    and-   (S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol;    or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention includes a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

One aspect of the present invention includes a method for treating aRAGE-mediated disease comprising administering to a subject a compoundof Formula (I) or a pharmaceutically acceptable salt thereof. Anotheraspect includes use of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for treatinga RAGE-mediated disease. A still further aspect includes a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of a RAGE-mediated disease. In one embodiment, the disease isAlzheimer's Disease. In one embodiment, such treatment modifies thepresentation of Alzheimer's Disease. In another embodiment, suchtreatment improves cognitive performance of a subject suffering frommild to moderate Alzheimer's Disease.

Pharmaceutically acceptable salts of the compounds of the presentinvention are also included within the scope of the invention. The term“pharmaceutically acceptable salt(s)” as used herein refers to non-toxicsalts of a compound of Formula (I) which are generally prepared byreacting the free base (i.e. free amine) of the compound of Formula (I)with a suitable organic or inorganic acid such as, but not limited to,hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate,succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate,methiodide, methobromide, methochloride, methanesulfonate,ethanesulfonate, picrate and the like, and include acids related to thepharmaceutically-acceptable salts listed in the Journal ofPharmaceutical Science, 66, 2 (1977) p. 1-19. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of the invention and these form a further aspect of theinvention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructure except for the replacement of a hydrogen atom by a deuteriumor tritium, or the replacement of a carbon atom by a ¹³C- or¹⁴C-enriched carbon are within the scope of the invention.

The compound of Formula (I) contains one chiral center. The scope of thepresent invention includes mixtures of stereoisomers as well as purifiedenantiomers or enantiomerically/diastereomerically enriched mixtures.Also included within the scope of the invention are the individualisomers of the compounds represented by the formulae of the presentinvention, as well as any wholly or partially equilibrated mixturesthereof. The present invention also includes any tautomers of thecompounds represented by the formulas above.

Examples of compounds of Formula (I) or a pharmaceutically acceptablesalt thereof having potentially useful biological activity are hereindescribed. The ability of compounds of Formula (I) or pharmaceuticallyacceptable salts thereof to inhibit the interaction of RAGE with itsphysiological ligands was established with representative compounds ofFormula (I) or a pharmaceutically acceptable salt thereof using theassay(s) described in the Examples section below.

The invention further provides pharmaceutical compositions comprising acompound of Formula (I) or a pharmaceutically acceptable salt thereof.The term “pharmaceutical composition” is used herein to denote acomposition that may be administered to a mammalian host, e.g., orally,topically, parenterally, by inhalation spray, or rectally, in unitdosage formulations containing conventional non-toxic carriers,diluents, adjuvants, vehicles and the like. The term “parenteral” asused herein, includes subcutaneous injections, intravenous,intramuscular, intracisternal injection, or by infusion techniques.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions or suspensions,lotions, eye ointments and eye or ear drops, impregnated dressings andaerosols etc., containing the compounds of the invention arecontemplated. These topical formulations may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 0.1% up to about 99% of the formulation. Moreusually they will form up to about 80% of the formulation. For thepurpose of this application, topical applications shall include mouthwashes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

Compounds that antagonize the interaction of RAGE with its physiologicalligands are potentially useful in treating diseases or conditions thatmay be responsive to the inhibiting of the RAGE receptor. The presentinvention provides a method of treatment comprising: administering to asubject a compound of Formula (I) or a pharmaceutically acceptable saltthereof. In an embodiment of this aspect, the present invention providesa method for the inhibition of the interaction of RAGE with itsphysiological ligands. In another embodiment of this aspect, the presentinvention provides a method for treating a disease state selected fromthe group consisting of acute and chronic inflammation including skininflammation such as psoriasis, atopic dermatitis, inflammationassociated with organ, tissue, or cell transplantation, and lunginflammation including, asthma and chronic obstructive pulmonarydisease, sepsis, diabetes, diabetes related complications, renalfailure, hyperlipidemic atherosclerosis associated with diabetes,neuronal cytotoxicity, restenosis, Down's syndrome, dementia associatedwith head trauma, amyotrophic lateral sclerosis, multiple sclerosis,amyloidosis, an autoimmune disease, wound healing, periodontal disease,neuropathy, neuronal degeneration, vascular permeability, nephropathy,atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction,tumor invasion and/or metastasis, and osteoporosis which comprisesadministering to a subject a therapeutically effective amount of acompound of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

I. RAGE and the Complications of Diabetes

As noted above, the compounds of the present invention are useful in thetreatment of the complications of diabetes. It has been shown thatnonenzymatic glycoxidation of macromolecules ultimately resulting in theformation of advanced glycation endproducts (AGEs) is enhanced at sitesof inflammation, in renal failure, in the presence of hyperglycemia andother conditions associated with systemic or local oxidant stress (Dyer,D., et al., J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al.,Biochem., 34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem.,266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol. Biol.,44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can occurfocally, as in the joint amyloid composed of AGE-β2-microglobulin foundin patients with dialysis-related amyloidosis (Miyata, T., et al., J.Clin. Invest., 92:1243-1252 (1993); Miyata, T., et al., J. Clin.Invest., 98:1088-1094 (1996)), or generally, as exemplified by thevasculature and tissues of patients with diabetes (Schmidt, A-M., etal., Nature Med., 1:1002-1004 (1995)). The progressive accumulation ofAGEs over time in patients with diabetes suggests that endogenousclearance mechanisms are not able to function effectively at sites ofAGE deposition. Such accumulated AGEs have the capacity to altercellular properties by a number of mechanisms. Although RAGE isexpressed at low levels in normal tissues and vasculature, in anenvironment where the receptor's ligands accumulate, it has been shownthat RAGE becomes upregulated (Li, J. et al., J. Biol. Chem.,272:16498-16506 (1997); Li, J., et al., J. Biol. Chem., 273:30870-30878(1998); Tanaka, N., et al., J. Biol. Chem. 275:25781-25790(2000)). RAGEexpression is increased in endothelium, smooth muscle cells andinfiltrating mononuclear phagocytes in diabetic vasculature. Also,studies in cell culture have demonstrated that AGE-RAGE interactioncaused changes in cellular properties important in vascular homeostasis.

II. RAGE and Cellular Dysfunction in the Amyloidoses

Also as noted above, the compounds of the present invention are usefulin treating amyloidoses and/or Alzheimer's Disease. RAGE appears to be acell surface receptor which binds β-sheet fibrillar material regardlessof the composition of the subunits (amyloid-β peptide, Aβ, amylin, serumamyloid A, prion-derived peptide) (Yan, S.-D., et al., Nature,382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)).Deposition of amyloid has been shown to result in enhanced expression ofRAGE. For example, in the brains of patients with Alzheimer's disease(AD), RAGE expression increases in neurons and glia (Yan, S.-D., et al.,Nature 382:685-691 (1996)). The consequences of Aβ interaction with RAGEappear to be quite different on neurons versus microglia. Whereasmicroglia become activated as a consequence of Aβ-RAGE interaction, asreflected by increased motility and expression of cytokines, earlyRAGE-mediated neuronal activation is superceded by cytotoxicity at latertimes. Further evidence of a role for RAGE in cellular interactions ofAβ concerns inhibition of Aβ-induced cerebral vasoconstriction andtransfer of the peptide across the blood-brain barrier to brainparenchyma when the receptor was blocked (Kumar, S., et al., Neurosci.Program, p 141 (2000)). Inhibition of RAGE-amyloid interaction has beenshown to decrease expression of cellular RAGE and cell stress markers(as well as NF-κB activation), and diminish amyloid deposition (Yan,S-D., et al., Nat. Med., 6:643-651 (2000)) suggesting a role forRAGE-amyloid interaction in both perturbation of cellular properties inan environment enriched for amyloid (even at early stages) as well as inamyloid accumulation.

In other studies using a mouse model of Alzheimer's Disease, it has beenshown that RAGE antagonists can reverse the formation of plaques and theloss of cognition. In U.S. Patent Publication No. US 2005/0026811, smallmolecule RAGE antagonists were used to inhibit the progression of Aβdeposition and reduced the volume of preexisting plaques in Alzheimer'sDisease mice (US 2005/0026811 at ¶¶ 581-586). Furthermore, treatmentwith such small molecule RAGE antagonists improved cognition in theseAlzheimer's Disease mouse models (US 2005/0026811 at ¶¶587-590). Thus,in a mouse model of Alzheimer's Disease, those mice who had developed Aβplaques and cognitive loss and were treated with small molecule RAGEantagonists exhibited a reduction in plaque volume and an improvement incognitive performance as compared to those Alzheimer's Disease mice whowere not treated with the small molecule RAGE antagonists, showing thatthe RAGE antagonist compounds may delay or slow loss of cognitiveperformance, or may improve cognitive performance of a subject sufferingfrom dementia of Alzheimer's type.

Also, it had been shown in both cellular assays and in animal studiesthat RAGE mediates the transcytosis of circulating Aβ across theblood-brain barrier (BBB). Such increased transcytosis of Aβ results inneuronal oxidant stress and sustained reductions in cerebral blood flow.The effects of RAGE can be inhibited by a RAGE modulator (e.g.,anti-RAGE antibody or sRAGE) (see e.g., Mackic et al., J. Clin. Invest.,102:734-743 (1998); see also Kumar et al., Neurosci., Program, p 141(2000)). These finding were confirmed by additional studies (see e.g.,U.S. Pat. No. 6,825,164 at col. 17, line 48 to col. 18, line 43; Deaneet al., Nature Medicine, 9:907-913 (2003)). Reduced cerebral perfusioncan promote ischemic lesions which can act synergistically with Aβ toexacerbate dementia. Also, insufficient cerebral blood flow may alter Aβtrafficking across the blood brain barrier thereby reducing Aβ clearanceand promoting accumulation of Aβ in brain (see Girouard and ladecola, J.Appl. Physiol., 100, 328-335 (2006) at page 332). Thus, the increase incerebral blood flow promoted by RAGE antagonists may reduce the symptomsor delay onset of development of Alzheimer's Disease, or both. Forexample, RAGE antagonists may delay or slow loss of cognitiveperformance, or may improve cognitive performance of a subject sufferingfrom dementia of Alzheimer's type, or both.

III. RAGE and Propagation of the Immune/Inflammatory Response

As noted above, the compounds of the present invention are useful intreating inflammation. For example, S100/calgranulins have been shown tocomprise a family of closely related calcium-binding polypeptidescharacterized by two EF-hand regions linked by a connecting peptide(Schafer, B. et al., TIBS, 21:134-140 (1996); Zimmer, D., et al., BrainRes. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem.,272:9496-9502 (1997); Lugering, N., et al., Eur. J. Clin. Invest.,25:659-664 (1995)). Although they lack signal peptides, it has long beenknown that S100/calgranulins gain access to the extracellular space,especially at sites of chronic immune/inflammatory responses, as incystic fibrosis and rheumatoid arthritis. RAGE is a receptor for manymembers of the S100/calgranulin family, mediating their proinflammatoryeffects on cells such as lymphocytes and mononuclear phagocytes. Also,studies on delayed-type hypersensitivity response, colitis in IL-10 nullmice, collagen-induced arthritis, and experimental autoimmuneencephalitis models suggest that RAGE-ligand interaction (presumablywith S100/calgranulins) has a proximal role in the inflammatory cascadeas implicated in the inflammatory diseases such as but not limited torheumatoid arthritis and multiple sclerosis.

RAGE is also implicated in inflammatory diseases of the skin such as butnot limited to atopic dermatitis, eczema, and psoriasis. Psoriasis inparticular is characterized by inflamed itchy lesions. Psoriasis may beaccompanied by arthropathic symptoms that are similar to those in seenin rheumatoid arthritis. There is considerable evidence that psoriasisis a polygenic autoimmune disorder. Psoriatic lesions are rich incytokines, in particular IL-1 and IL-8, both potent proinflammatorymediators. IL-8 in particular is a chemotactic factor for neutrophils;neutrophils are also known to synthesize and secrete S100 proteins, oneof the ligands for RAGE which is implicated in propagation of the immuneand inflammatory response. Psoriasin, (S100A7) a new member of the S100gene family, is a secreted protein isolated from psoriatic skin.Semprini et al. (Hum. Genet. 2002 October, 111(4-5), 310-3) have shown alinkage of psoriasis genetic susceptibility to distinct overexpressionof S100 proteins in skin. Therefore, a modulator of RAGE would beexpected to regulate the immune response in psoriasis.

IV. RAGE and Amphoterin

As noted above, the compounds of the present invention are useful intreating tumor and tumor metastasis. For example, amphoterin is a highmobility group I nonhistone chromosomal DNA binding protein (Rauvala,H., et al., J. Biol. Chem., 262:16625-16635 (1987); Parkikinen, J., etal., J. Biol. Chem. 268:19726-19738 (1993)) which has been shown tointeract with RAGE. It has been shown that amphoterin promotes neuriteoutgrowth, as well as serving as a surface for assembly of proteasecomplexes in the fibrinolytic system (also known to contribute to cellmobility). In addition, a local tumor growth inhibitory effect ofblocking RAGE has been observed in a primary tumor model (C6 glioma),the Lewis lung metastasis model (Taguchi, A., et al., Nature 405:354-360(2000)), and spontaneously arising papillomas in mice expressing thev-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad. Sci.,87:9178-9182 (1990)).

V. RAGE and Respiratory Diseases

Airway inflammation is important in the pathogenesis of asthma. Suchinflammation may give rise to significant exacerbations and increases inasthma severity, as well as to be a major factor in a decline inasthmatic status. In severe exacerbations of asthma there is an intense,mechanistically heterogeneous inflammatory response involving neutrophiland eosinophil accumulation and activation. Neutrophils are asignificant source of S100 proteins, key ligands for RAGE implicated inthe propagation of the immune response and inflammation. Therefore,modulators of RAGE would be expected to possess therapeutic value in thetreatment of asthma. Further, the propagation step in the immuneresponse in the lung driven by S100—RAGE interaction would be expectedto lead to the activation and/or recruitment of inflammatory cells, suchas neutrophils, which in chronic obstructive pulmonary diseases such asemphysema, are significant sources of damaging proteases. Therefore, aRAGE modulator would be expected possess potential in the treatment ofchronic obstructive pulmonary diseases.

As used herein, the phrase “therapeutically effective amount” shall meanthat amount of a drug or pharmaceutical agent that will elicit thetherapeutic response of an subject that is being sought.

In these methods, factors which may influence what constitutes atherapeutically effective amount include, but are not limited to, thesize and weight of the subject, the biodegradability of the therapeuticagent, the activity of the therapeutic agent, the size of the effectedarea, as well as its bioavailability. The phrase includes amounts which,as compared to a corresponding subject who has not received such amount,results in improved treatment, healing, or amelioration of a sideeffect, or a decrease in the rate of advancement of a disease ordisorder.

In an embodiment, the present invention provides a method for treatingrestenosis comprising: administering to a subject a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. In an embodiment, the subject is suffering fromdiabetes.

In an embodiment, the present invention provides a method for treatingacute or chronic inflammation comprising: administering to a subject atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In an embodiment, the present invention provides a method for treatingdementia associated with head trauma comprising: administering to asubject a therapeutically effective amount of a compound of Formula (I)or a pharmaceutically acceptable salt thereof. In an embodiment, thecognitive performance of the subject is improved. In another embodiment,the cognitive performance of the subject is maintained. In anotherembodiment, the rate of loss of cognitive performance of the subject isslowed.

In an embodiment, the present invention provides a method for treatingAlzheimer's Disease comprising: administering to a subject atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof. With respect to Alzheimer'sDisease, the present invention is believed useful in alteration thecourse of the underlying dementing process. Alzheimer's Disease may bediagnosed by NINCDS and DSM criteria, Mini-Mental State Examination, andClinical Dementia Rating within particular limits. One aspect of thepresent invention includes improving cognitive performance comprisingadministering a compound of Formula (I) or a pharmaceutically acceptablesalt thereof. Cognitive performance may be assessed with the cognitivesubscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), as isknown in the art, which scores cognitive function on a 0 to 70 scale,with higher scores indicating greater cognitive impairment. Thus, areduction in score demonstrates cognitive improvement. One aspect of thepresent invention includes administering to a subject a compound ofFormula (I) or a pharmaceutically acceptable salt thereof to reduce anADAS-cog score of a subject in need of such reduction. Such a subjectmay be a human be suffering from dementia of Alzheimer's type, mild tomoderate Alzheimer's Diseases, or severe Alzheimer's Disease.

In addition, the progression of Alzheimer's Disease may also be assessedin a human through examination of four areas of function: General,Cognitive, Behavioral, and Activities of Daily Living. Such anassessment may be performed using a Clinician's Interview BasedImpression of Change (CIBIC or CIBIC plus). One aspect of the presentinvention includes improvement in subject's function comprisingadministering a compound of Formula (I) or a pharmaceutically acceptablesalt thereof. In one embodiment, the subject's function is one or moreof general, cognitive, behavioral, and activities of daily living.

In an embodiment, the present invention provides a method for improvingwound healing in a diabetic subject comprising: administering to thesubject a therapeutically effective amount of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, so as to improve the rateof wound healing in the subject relative to an untreated wound.

In an embodiment, the present invention provides a method for treatingin a subject inflammation associated with transplantation of an organ, atissue or a plurality of cells from a first site to a second sitecomprising: administering to the subject a therapeutically effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof, so as to reduce inflammation in the subject. In anembodiment, the first and second sites are in different subjects. Inanother embodiment, the first and second sites are in the same subject.In another embodiment, the transplanted organ, cells or tissue comprisea cell or tissue of a pancreas, skin, liver, kidney, heart, bone marrow,blood, bone, muscle, artery, vein, cartilage, thyroid, nervous system,or stem cells.

In another embodiment, at least one compound of Formula (I) or apharmaceutically acceptable salt thereof is utilized, either alone or incombination with one or more known therapeutic agents

As used herein, the phrase “a subject” refers to mammalian subjects,preferably humans, who either suffer from one or more of the aforesaiddiseases or disease states or are at risk for such.

In a further aspect of the present invention, the RAGE inhibitors of theinvention may be used in adjuvant therapeutic or combination therapeutictreatments with other known therapeutic agents.

The following is a non-exhaustive listing of adjuvants and additionaltherapeutic agents which may be utilized in combination with the RAGEinhibitors of the present invention:

Pharmacologic classifications of anticancer agents:

-   -   1. Alkylating agents: Cyclophosphamide, nitrosoureas,        carboplatin, cisplatin, procarbazine    -   2. Antibiotics: Bleomycin, Daunorubicin, Doxorubicin    -   3. Antimetabolites: Methotrexate, Cytarabine, Fluorouracil    -   4. Plant alkaloids: Vinblastine, Vincristine, Etoposide,        Paclitaxel,    -   5. Hormones: Tamoxifen, Octreotide acetate, Finasteride,        Flutamide    -   6. Biologic response modifiers: Interferons, Interleukins,        Anti-tumor antibodies

Pharmacologic classifications of treatment for Rheumatoid Arthritis(Inflammation)

-   -   1. Analgesics: Aspirin    -   2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,        Naproxen, Diclofenac    -   3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,        gold preparations, hydroxychloroquine, sulfasalazine    -   4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab        Glucocorticoids

Pharmacologic classifications of treatment for Diabetes Mellitus

-   -   1. Sulfonylureas: Tolbutamide, Tolazamide, Glyburide, Glipizide    -   2. Biguanides: Metformin    -   3. Miscellaneous oral agents: Acarbose, Troglitazone    -   4. Insulin

Pharmacologic classifications of treatment for Alzheimer's Disease

-   -   1. Cholinesterase Inhibitor: Tacrine, Donepezil    -   2. Antipsychotics: Haloperidol, Thioridazine    -   3. Antidepressants: Desipramine, Fluoxetine, Trazodone,        Paroxetine    -   4. Anticonvulsants: Carbamazepine, Valproic acid

In a further embodiment, the present invention provides a method oftreating a RAGE mediated disease, the method comprising administering toa subject a therapeutically effective amount of a compound of Formula(I) or a pharmaceutically acceptable salt thereof in combination with atherapeutic agent selected from the group consisting of alkylatingagents, antimetabolites, plant alkaloids, antibiotics, hormones,biologic response modifiers, analgesics, NSAIDs, DMARDs,glucocorticoids, sulfonylureas, biguanides, insulin, cholinesteraseinhibitors, antipsychotics, antidepressants, and anticonvulsants.

In a further embodiment, the present invention provides thepharmaceutical composition of the invention as described above, furthercomprising one or more therapeutic agents selected from the groupconsisting of alkylating agents, antimetabolites, plant alkaloids,antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs,DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin,cholinesterase inhibitors, antipsychotics, antidepressants, andanticonvulsants.

Such other therapeutic agents may be administered by a like route ordifferent route that the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. Where a compound of Formula (I) or apharmaceutically acceptable salt thereof is used in combination withanother therapeutic agent, the composition may contain the compound ofFormula (I) or a pharmaceutically acceptable salt thereof in combinationwith the other therapeutic agent(s). Alternatively, where separatedosage formulations are used, the compound of Formula (I) or apharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents may be administered at essentially the same time(e.g., concurrently) or at separately staggered times (e.g.,sequentially).

Generally speaking, a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof may be administered at a dosage level of fromabout 0.003 to 500 mg/kg of the body weight of the subject beingtreated. In an embodiment, a compound of Formula (I) or apharmaceutically acceptable salt thereof may be administered at a dosagerange between about 0.003 and 200 mg/kg of body weight per day. In anembodiment, a compound of Formula (I) or a pharmaceutically acceptablesalt thereof may be administered at a dosage range between about 0.1 to100 mg/kg of body weight per day. The amount of active ingredient thatmay be combined with the carrier materials to produce a single dosagemay vary depending upon the host treated and the particular mode ofadministration. For example, a formulation intended for oraladministration to humans may contain 1 mg to 2 grams of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof with anappropriate and convenient amount of carrier material which may varyfrom about 5 to 95 percent of the total composition. A dosage formintended for topical administration to the skin may be prepared at 0.1%to 99% compound to topical excipient ratio. A dosage form intended forinhaled administration of 0.01 to 200 mg of compound in a suitablecarrier to deliver an inhaled dosage of compound. Dosage unit forms ofsystemically delivered compound may generally contain between from about5 mg to about 500 mg of active ingredient. This dosage may beindividualized by the clinician based on the specific clinical conditionof the subject being treated. Thus, it will be understood that thespecific dosage level for any particular subject will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination, size of effected area and the severity of the particulardisease undergoing therapy.

The compounds of this invention may be made by a variety of methods wellknown to those of ordinary skill in the art including the methods areset out below in the Examples.

In another aspect, the present invention also provides a method for thesynthesis of compounds useful as intermediates in the preparation ofcompounds of the present invention along with methods for theirpreparation.

In an embodiment, the present invention provides a method forsynthesizing a compound of Formula (I) or a pharmaceutically acceptablesalt thereof

comprising: mixing a compound of Formula (X)

and an amine having the formula R¹R²NH,

-   -   wherein    -   R¹ and R² are independently selected from the group consisting        of —CH₃, —CH₂CH₃, —CH(CH₃)₂, and —CH₂CH₂CH₃; and    -   Q¹ is selected from the group consisting of —CH₂OCH₂CH₃ and        —CH₂CH₂CH₂CH₃.

-   In an embodiment of the method of synthesis, R¹ and R² are the same.

-   In another embodiment of the method of synthesis, R¹ and R² are    —CH₃.

-   In another embodiment of the method of synthesis, R¹ and R² are    —CH₂CH₃.

-   In another embodiment of the method of synthesis, Q¹ is —CH₂OCH₂CH₃.

-   In another embodiment of the method of synthesis, Q¹ is    —CH₂CH₂CH₂CH₃.

-   In another embodiment of the method of synthesis, the compound of    Formula (X) is in the S configuration.

-   In another embodiment of the method of synthesis, the compound of    Formula (X) is in the R configuration.

-   In another embodiment of the method of synthesis, mixture of the    compound of Formula (X) and R¹R²NH is heated above room temperature.    In a further embodiment, the mixture may be heated with microwave    radiation.

-   In another embodiment of the method of synthesis, the compound of    Formula (X) and R¹R²NH are mixed in a solvent. The solvent may be    selected from an aprotic solvent. A suitable aprotic solvent    includes THF.

EXAMPLES

LC-MS data were obtained using gradient elution on a parallel MUX™system, running four Waters 1525 binary HPLC pumps, equipped with aMux-UV 2488 multichannel UV-Vis detector (recording at 215 and 254 nM)and a Leap Technologies HTS PAL Auto sampler using a Sepax GP-C18 4.6×50mm column. A three minute gradient may be run from 25% of solution B(97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% of solution A (97.5%water, 2.5% acetonitrile, 0.05% TFA) to 100% of solution B. The systemis interfaced with a Waters Micromass ZQ mass spectrometer usingelectrospray ionization. All MS data was obtained in the positive modeunless otherwise noted.

¹H NMR data was obtained on a Varian 400 MHz spectrometer.

Abbreviations used in the Examples are as follows:

-   d=day-   DCM=dichloromethane-   DMF=N, N-dimethylformamide-   DMSO=dimethylsulfoxide-   ELISA=enzyme-linked-   immunosorbent assay-   ether=diethyl ether-   EtOAc=ethyl acetate-   g=gram-   h=hour-   Hz=hertz-   L=liter-   LC=liquid chromatography-   M=molar-   m/z=mass to charge ratio-   MeOH=methanol-   mg=milligram-   min=minute-   mL=milliliter-   mM=millimolar-   mmol=millimole-   mol=mole-   MS=mass spectrometry-   N=normal-   NMR=nuclear magnetic resonance-   spectroscopy-   ppm=parts per million-   rt or RT=room temperature-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Intermediate A14-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol

Pyridinium bromide perbromide (33.6 g, 0.105 mole) was added to asolution of 4-acetylphenyl acetate (17.8 g, 0.1 mole) in dioxane (100mL). The heterogeneous mixture was stirred for 5 hours. During thecourse of the reaction the intensity of the red color decreased and awhite solid was formed. The reaction mixture was diluted with ether (200mL) and washed with water (3×100 mL), brine (75 mL), dried (MgSO₄) andremoved in vacuo to give the desired product as an oil, which solidifiedupon standing at room temperature (26.0 g). This product was used in thenext transformation without further purification.

A solution of acetic acid 4-(2-bromo-acetyl)-phenyl ester (8.6 g, 33.6mmol) in DCM (20 mL) was added to a mixture of4-(4-chlorophenoxy)aniline (6.4 g, 29.2 mmol) and NaHCO₃ (4.2 g, 50mmol) in methanol (100 mL). The formation of a yellow precipitateoccurred after 1 h, but the reaction still did not go completion asindicated by both TLC and HPLC. The reaction mixture was further stirredovernight. The solvents were removed in vacuo and the residue was addedto ice-water (200 g). The flask was then rinsed with more water (100mL). After 1 hour, the yellow solid was collected by filtration andwashed with water (200 mL). The filtrate (water) in the filtering flaskwas removed and vacuum kept going on for an hour to remove most of thewater. To dry further, the solid was washed with isovaleryl ester, andthe amide of the unreacted aniline.

A solution of acetic acid4-{2-[4-(4-chloro-phenoxy)-phenylamino]-acetyl}-phenyl ester (79.17 g,200 mmol, 1.0 eq.) in dichloromethane (800 mL) and triethylamine (56 mL,400 mmol, 2.0 eq.) was cooled to −0° C. and treated with valerylchloride (35.6 mL, 300 mmol, 1.5 eq.). The reaction mixture was stirredand warmed to room temperature over 24 h. This reaction mixture was thenfurther treated with additional triethylamine (28 mL, 200 mmol, 1.0 eq.)and valeryl chloride (11.9 mL, 100 mmol, 0.5 eq.). Analysis of thereaction by TLC and LC/MS showed that some starting material remained,but the desired keto-amide was the major product. The reaction wasevaporated in vacuo, recharged with ethyl acetate and filtered. Thesolvent was evaporated in vacuo, and the residue was then purified byflash column chromatography over silica gel (EtOAc/hexanes˜25%). Theresultant oil was dissolved in ethyl acetate, washed with 1N HCl, driedand evaporated in vacuo. This material was then used as is in the nexttransformation.

A mixture of acetic acid4-(2-{[4-(4-chloro-phenoxy)-phenyl]-pentanoyl-amino}-acetyl)-phenylester (from above, based on 200 mmol) with ammonium acetate (308 g, 4000mmol, 20.0 eq) in acetic acid (300 mL) was stirred at 100-110° C.overnight. After completion of the reaction (indicated by HPLC), themixture was cooled below 60° C. and poured over ice. After stirring, thesolid was filtered, washed with diethyl ether (twice), ethyl acetate(twice), ether (once) and air dried, yielding ˜55.0 g (65.6%) of4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol as afinely divided off-white solid.

¹H-NMR (400 MHz; CDCl₃): δ 7.65 (d, 2H), 7.37 (d, 2H), 7.30 (d, 2H),7.13 (s, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.84 (d, 2H), 2.70-2.66 (m,2H), 1.69-1.61 (m, 2H), 1.33-1.28 (m, 2H), 0.86 (t, 3H).

Intermediate A22-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole

A mixture of4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol(0.42 g, 1.0 mmol, 1.0 eq.) and Cs₂CO₃ (1.0 g, 3.0 mmol, 3.0 eq.) in DMF(3 mL) was stirred and preheated to 80° C. The reaction mixture was thentreated with a solution of (2R)-(−)-glycidyl tosylate (0.27 g, 1.2 mmol,1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for˜30-60 min following completion of the addition. Analysis of thereaction by TLC and LC/MS showed that the starting phenol had beenconsumed and the desired alkylated-phenol was the major product. Thereaction was then cooled and diluted with EtOAc and washed with brine.The organic phase was dried with Na₂SO₄ and evaporated in vacuo. Thecrude alkylated-phenol was then purified by flash column chromatographyover silica gel (EtOAc/hexanes˜1:3).

¹H-NMR (400 MHz; CDCl₃): δ 7.72 (d, 2H), 7.36 (d, 2H), 7.30 (d, 2H),7.15 (s, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.94 (d, 2H), 4.26-4.22 (m,1H), 4.02-3.98 (m, 1H), 3.40-3.36 (m, 1H), 2.92-2.90 (m, 1H), 2.79-2.77(m, 1H), 2.69-2.65 (m, 2H), 1.71-1.63 (m, 2H), 1.37-1.27 (m, 2H), 0.86(t, 3H).

Intermediate A32-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole

A mixture of4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol(0.42 g, 1.0 mmol, 1.0 eq.) and Cs₂CO₃ (1.0 g, 3.0 mmol, 3.0 eq.) in DMF(3 mL) was stirred and preheated to 80° C. The reaction mixture was thentreated with a solution of (2S)-(+)-glycidyl tosylate (0.27 g, 1.2 mmol,1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for˜30-60 min following completion of the addition. Analysis of thereaction by TLC and LC/MS showed that the starting phenol had beenconsumed and the desired alkylated-phenol was the major product. Thereaction was then cooled and diluted with EtOAc and washed with brine.The organic phase was dried with Na₂SO₄ and evaporated in vacuo. Thecrude alkylated-phenol was then purified by flash column chromatographyover silica gel (EtOAc/hexanes˜1:3).

¹H-NMR (400 MHz; CDCl₃): δ 7.72 (d, 2H), 7.36 (d, 2H), 7.30 (d, 2H),7.15 (s, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.94 (d, 2H), 4.26-4.23 (m,1H), 4.01-3.98 (m, 1H), 3.40-3.36 (m, 1H), 2.93-2.91 (m, 1H), 2.79-2.77(m, 1H), 2.69-2.65 (m, 2H), 1.71-1.63 (m, 2H), 1.37-1.25 (m, 2H), 0.86(t, 3H).

Intermediate B14-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol

Pyridinium bromide perbromide (33.6 g, 0.105 mole) was added to asolution of 4-acetylphenyl acetate (17.8 g, 0.1 mole) in dioxane (100mL). The heterogeneous mixture was stirred for 5 hours. During thecourse of the reaction the intensity of the red color decreased and awhite solid was formed. The reaction mixture was diluted with ether (200mL) and washed with water (3×100 mL), brine (75 mL), dried (MgSO₄) andremoved in vacuo to give the desired product as an oil, which solidifiedupon standing at room temperature (26.0 g). This product was used in thenext transformation without further purification.

A solution of acetic acid 4-(2-bromo-acetyl)-phenyl ester (8.6 g, 33.6mmol) in DCM (20 mL) was added to a mixture of4-(4-chlorophenoxy)aniline (6.4 g, 29.2 mmol) and NaHCO₃ (4.2 g, 50mmol) in methanol (100 mL). The formation of a yellow precipitateoccurred after 1 h, but the reaction still did not go completion asindicated by both TLC and HPLC. The reaction mixture was further stirredovernight. The solvents were removed in vacuo and the residue was addedto ice-water (200 g). The flask was then rinsed with more water (100mL). After 1 hour, the yellow solid was collected by filtration andwashed with water (200 mL). The filtrate (water) in the filtering flaskwas removed and vacuum kept going on for an hour to remove most of thewater. To dry further, the solid was washed with isovaleryl ester, andthe amide of the unreacted aniline.

A solution of acetic acid4-{2-[4-(4-chloro-phenoxy)-phenylamino]-acetyl}-phenyl ester (0.33 mmol,1.0 eq.) in THF (3 mL) was cooled to −78° C., treated with ethoxyacetylchloride (0.33 mmol, 1.0 eq.) and stirred for ˜5 min. This cold reactionmixture was then treated with pyridine (0.33 mmol, 1.0 eq.) dropwise andallowed to stir for ˜1 h. Analysis of the reaction by TLC and LC/MSshowed that the starting material has been consumed and the desiredketo-amide was the major product. The reaction was then diluted withEt₂O and washed with H₂O, the organic phase was dried with Na₂SO₄ andevaporated in vacuo, and the crude keto-aniline was used in thesubsequent step without further purification.

A mixture ofN-(4-chlorophenoxyphenyl)-N-(4-acetoxybenzoylmethyl)-n-pentanamide(0.1011 mol, 1.0 eq) and ammonium acetate (175 g, 2.27 mol, 22.4 eq) inacetic acid (150 mL) was heated at 100-110° C. After completion of thereaction as indicated by HPLC or TLC, the mixture was cooled below 60°C. and is added to chilled water. The solid was filtered, washed withwater and ethyl acetate and air dried to produce the desired4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol.

Intermediate B21-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole

A mixture of4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol(0.21 g, 0.5 mmol, 1.0 eq.) and Cs₂CO₃ (0.49 g, 1.5 mmol, 3.0 eq.) inDMF (2 mL) was stirred and preheated to 80° C. The reaction mixture wasthen treated with a solution of (2R)-(−)-glycidyl tosylate (0.17 g, 0.75mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C.for ˜30 min following completion of the addition. Analysis of thereaction by TLC and LC/MS showed that the starting phenol had beenconsumed and the desired alkylated-phenol was the major product. Thereaction was then cooled and diluted with EtOAc and washed with brine.The organic phase was dried with Na₂SO₄ and evaporated in vacuo. Thecrude alkylated-phenol was then purified by flash column chromatographyover silica gel (EtOAc/hexanes˜1:3).

¹H-NMR (400 MHz; CDCl₃): δ 7.74 (d, 2H), 7.49 (d, 2H), 7.36 (d, 2H),7.28 (s, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.95 (d, 2H), 4.48 (s, 2H),4.27-4.23 (m, 1H), 4.03-3.99 (m, 1H), 3.62-3.57 (m, 2H), 3.40-3.37 (m,1H), 2.94-2.92 (m, 1H), 2.80-2.78 (m, 1H), 1.21 (t, 3H).

Intermediate B31-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole

A mixture of4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol(0.21 g, 0.5 mmol, 1.0 eq.) and Cs₂CO₃ (0.49 g, 1.5 mmol, 3.0 eq.) inDMF (2 mL) was stirred and preheated to 80° C. The reaction mixture wasthen treated with a solution of (2S)-(+)-glycidyl tosylate (0.17 g, 0.75mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C.for ˜30 min following completion of the addition. Analysis of thereaction by TLC and LC/MS showed that the starting phenol had beenconsumed and the desired alkylated-phenol was the major product. Thereaction was then cooled and diluted with EtOAc and washed with brine.The organic phase was dried with Na₂SO₄ and evaporated in vacuo. Thecrude alkylated-phenol was then purified by flash column chromatographyover silica gel (EtOAc/hexanes˜1:3).

¹H-NMR (400 MHz; CDCl₃): δ 7.74 (d, 2H), 7.49 (d, 2H), 7.36 (d, 2H),7.28 (s, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.95 (d, 2H), 4.48 (s, 2H),4.27-4.24 (m, 1H), 4.03-3.99 (m, 1H), 3.62-3.57 (m, 2H), 3.40-3.37 (m,1H), 2.94-2.92 (m, 1H), 2.80-2.78 (m, 1H), 1.20 (t, 3H).

Example 1(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(100 mg, 2.1 mmol, from intermediate A2) in 3 mL of dimethylamine in THF(2M) was stirred at 76° C. for 1 h in a microwave reactor. Uponcompletion (determined by LC/MS), the reaction was evaporated in vacuoand purified by silica gel flash column chromatography using a gradientof EtOAc to 96% EtOAc/(2M NH₃/MeOH) as an eluent to afford(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.62 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.39 (m, 1H), 4.09 (d,2H), 3.37 (d, 2H), 2.98-2.96 (m, 8H), 1.69-1.66 (m, 2H), 1.37-1.31 (m,2H), 0.88 (t, 3H).

Example 2(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(100 mg, 2.1 mmol, from intermediate A2) in 1 mL of diethylamine and 2mL of THF was stirred at 76° C. for 1 h in a microwave reactor. Uponcompletion (determined by LC/MS), the reaction was evaporated in vacuoand purified by silica gel flash column chromatography using a gradientof EtOAc to 96% EtOAc/(2M NH₃/MeOH) as an eluent to afford(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.45 (d, 2H), 7.24 (d, 2H), 7.17-7.10 (m, 4H), 4.42-4.38 (m, 1H), 4.11(d, 2H), 3.45-3.27 (m, 6H), 2.97 (t, 2H), 1.72-1.64 (m, 2H), 1.39-1.30(m, 8H), 0.89 (t, 3H).

Example 3(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(from intermediate A3) in 3 mL of dimethylamine in THF (2M) was stirredat 76° C. for 1 h in a microwave reactor. Upon completion (determined byLC/MS), the reaction was evaporated in vacuo and purified by silica gelflash column chromatography using a gradient of EtOAc to 96% EtOAc/(2MNH₃/MeOH) as an eluent to afford(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.38 (m, 1H), 4.09 (d,2H), 3.37 (d, 2H), 2.98-2.96 (m, 8H), 1.71-1.63 (m, 2H), 1.37-1.30 (m,2H), 0.88 (t, 3H).

Example 4(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(from intermediate A3) in 1 mL of diethylamine and 2 mL of THF wasstirred at 76° C. for 1 h in a microwave reactor. Upon completion(determined by LC/MS), the reaction was evaporated in vacuo and purifiedby silica gel flash column chromatography using a gradient of EtOAc to96% EtOAc/(2M NH₃/MeOH) as an eluent to afford(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.45 (d, 2H), 7.24 (d, 2H), 7.16-7.10 (m, 4H), 4.42-4.37 (m, 1H), 4.10(d, 2H), 3.42-3.26 (m, 6H), 2.96 (t, 2H), 1.71-1.63 (m, 2H), 1.38-1.31(m, 8H), 0.88 (t, 3H).

Example 5(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(˜100 mg, ˜0.20 mmol, from intermediate B2) in 3 mL of dimethylamine inTHF (2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.05 (s, 1H), 7.75 (d, 2H), 7.65 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.69 (s, 2H), 4.42-4.36(m, 1H), 4.11 (d, 2H), 3.60 (q, 2H), 3.37 (d, 2H), 2.99 (s, 3H), 2.96(s, 3H) 1.20 (t, 3H).

Example 6(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(˜100 mg, ˜0.20 mmol, from intermediate B3) in 3 mL of dimethylamine inTHF (2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.05 (s, 1H), 7.76 (d, 2H), 7.65 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.69 (s, 2H), 4.42-4.36(m, 1H), 4.10 (d, 2H), 3.60 (q, 2H), 3.37 (d, 2H), 2.99 (s, 3H), 2.96(s, 3H) 1.20 (t, 3H).

Example 7(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(˜100 mg, ˜0.20 mmol, from intermediate B2) in 1 mL of diethylamine and2 mL of THF was stirred at 60° C. overnight in a teflon-capped vial.Upon completion (determined by LC/MS), the reaction was dried in vacuoand purified by silica gel flash column chromatography using a gradientof EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.06 (s, 1H), 7.76 (d, 2H), 7.66 (d, 2H),7.43 (d, 2H), 7.22 (d, 2H), 7.16 (d, 2H), 7.10 (d, 2H), 4.69 (s, 2H),4.42-4.36 (m, 1H), 4.11 (d, 2H), 3.62-3.56 (q, 2H), 3.41-3.24 (m 6H),1.36 (t, 6H), 1.19 (t, 3H).

Example 8(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(˜100 mg, ˜0.20 mmol, from intermediate B3) in 1 mL of diethylamine and2 mL of THF was stirred at 60° C. overnight in a teflon-capped vial.Upon completion (determined by LC/MS), the reaction was dried in vacuoand purified by silica gel flash column chromatography using a gradientof EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.06 (s, 1H), 7.75 (d, 2H), 7.65 (d, 2H),7.43 (d, 2H), 7.22 (d, 2H), 7.16 (d, 2H), 7.10 (d, 2H), 4.69 (s, 2H),4.42-4.36 (m, 1H), 4.11 (d, 2H), 3.62-3.56 (q, 2H), 3.41-3.24 (m, 6H),1.36 (t, 6H), 1.19 (t, 3H).

Example 9(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate A2) in 4 mL of methylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.43 (d, 2H), 7.23 (d, 2H), 7.15-7.10 (m, 4H), 4.34-4.24 (m, 1H),4.14-4.06 (m, 2H), 3.30-3.16 (m, 2H), 2.96 (t, 2H), 2.76 (s, 3H),1.70-1.63 (m, 2H), 1.40-1.28 (m, 2H), 0.87 (t, 3H).

Example 10(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate A3) in 4 mL of methylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.43 (d, 2H), 7.23 (d, 2H), 7.15-7.10 (m, 4H), 4.34-4.24 (m, 1H),4.12-4.06 (m, 2H), 3.30-3.16 (m, 2H), 2.96 (t, 2H), 2.76 (s, 3H),1.70-1.63 (m, 2H), 1.40-1.28 (m, 2H), 0.87 (t, 3H).

Example 11(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate A2) in 4 mL of ethylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.15-7.10 (m, 4H), 4.34-4.24 (m, 1H),4.14-4.06 (m, 2H), 3.34-3.28 (m, 1H), 3.19-3.11 (m, 3H), 2.96 (t, 2H),1.71-1.63 (m, 2H), 1.38-1.30 (m, 5H), 0.88 (t, 3H).

Example 12(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-oldihydrochloride

A solution of2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate A3) in 4 mL of ethylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 7.90 (s, 1H), 7.73 (d, 2H), 7.61 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.34-4.24 (m, 1H),4.14-4.06 (m, 2H), 3.34-3.28 (m, 1H), 3.18-3.11 (m, 3H), 2.96 (t, 2H),1.71-1.63 (m, 2H), 1.38-1.29 (m, 5H), 0.88 (t, 3H).

Example 13(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate B2) in 4 mL of methylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.06 (s, 1H), 7.75 (d, 2H), 7.65 (d, 2H),7.43 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.69 (s, 2H), 4.31-4.26(m, 1H), 4.13-4.07 (m, 2H), 3.60 (q, 2H), 3.32-3.28 (m, 1H), 3.21-3.15(m, 1H), 2.76 (s, 3H), 1.19 (t, 3H).

Example 14(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate B3) in 4 mL of methylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.06 (s, 1H), 7.75 (d, 2H), 7.65 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.69 (s, 2H), 4.31-4.26(m, 1H), 4.13-4.07 (m, 2H), 3.60 (q, 2H), 3.32-3.28 (m, 1H), 3.21-3.15(m, 1H), 2.76 (s, 3H), 1.20 (t, 3H).

Example 15(R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate B2) in 4 mL of ethylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(R)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.02 (s, 1H), 7.75 (d, 2H), 7.64 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.67 (s, 2H), 4.29-4.25(m, 1H), 4.13-4.06 (m, 2H), 3.60 (q, 2H), 3.32-3.28 (m 1H), 3.19-3.11(m, 3H), 1.35 (t, 3H), 1.20 (t, 3H).

Example 16(S)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-oldihydrochloride

A solution of1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole(50 mg, 0.11 mmol, from intermediate B3) in 4 mL of ethylamine in MeOH(2M) was stirred at 60° C. overnight in a teflon-capped vial. Uponcompletion (determined by LC/MS), the reaction was dried in vacuo andpurified by silica gel flash column chromatography using a gradient ofEtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford(S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.

The resultant free base was converted to the correspondingdihydrochloride salt by dissolution in 1 mL of DCM and 3 mL ofHCl/dioxane (4.0 M) and removal of solvent in vacuo.

¹H-NMR (400 MHz; CD₃OD): δ 8.04 (s, 1H), 7.75 (d, 2H), 7.65 (d, 2H),7.44 (d, 2H), 7.23 (d, 2H), 7.16-7.10 (m, 4H), 4.68 (s, 2H), 4.29-4.25(m, 1H), 4.13-4.06 (m, 2H), 3.60 (q, 2H), 3.32-3.28 (m 1H), 3.19-3.11(m, 3H), 1.35 (t, 3H), 1.20 (t, 3H).

Example Z[3-(4-{2-butyl-1-[4-(4-chlorophenoxy)-phenyl]-1H-imidazole-4-yl}-phenoxy)-propyl]-diethyl-aminedihydrochloride

Example Z may be prepared according to the method described in PCTpublication number WO 2003/075921 for Example 406.

Biological Assay

The following assay method may be used to identify compounds of Formula(I) or pharmaceutically acceptable salts thereof which are useful asinhibitors of binding of physiological RAGE ligands, such as S100b andβ-amyloid, to RAGE.

S100b, β-amyloid, or CML (500 ng/100 μL/well) in 100 mM sodiumbicarbonate/sodium carbonate buffer (pH 9.8) is loaded onto the wells ofa NUNC Maxisorp flat bottom 96—well microtitre plate. The plate isincubated at 4° C. overnight. The wells are aspirated and treated with50 mM imidazole buffer saline (pH 7.2) (with 5 mM CaCl₂/MgCl₂)containing 1% bovine serum albumin (BSA) (300 μL/well) for 1 h at RT.The wells are aspirated.

Test compounds are dissolved in nanopure water (concentration: 10-100μM). DMSO may be used as co-solvent. 25 μL of test compound solution in4% DMSO is added, along with 75 μL sRAGE (6 nM FAC) to each well andsamples are incubated for 1 h at 37° C. The wells are washed severaltimes with 155 mM NaCl pH 7.2 buffer saline and are soaked for severalseconds between each wash.

Non-radioactive detection is performed by adding:

10 μL Biotinylated goat F(ab′)2 Anti-mouse IgG. (8.0×10-4 mg/mL, FAC), 5μL Alk-phos-Streptavidin (3×10-3 mg/mL FAC), 0.42 μL per 5 mL Monoclonalantibody for sRAGE (FAC 6.0×10-3 mg/mL) to 5 mL 50 mM imidazole buffersaline (pH 7.2) containing 0.2% bovine serum albumin and 5 mM CaCl₂. Themixture is incubated for 30 minutes at RT.

100 μL of complex is added to each well and incubation is allowed toproceed at rt for 1 h. Wells are washed several times with wash bufferand soaked several seconds between each wash. 100 μL 1 mg/mL (pNPP) in 1M diethanolamine (pH adjusted to 9.8 with HCl) is added. Color isallowed to develop in the dark for 30 min to 1 h at rt. The reaction isquenched with 10 μL of stop solution (0.5-1.0 N NaOH in 50% ethanol) andthe absorbance is measured spectrophotometrically with a microplatereader at 405 nm.

The Examples 1-16 (hydrochloride salt form) were tested according to theassay method described above, employing S100b or β-amyloid as the RAGEligand, and were found to possess IC50 shown below. IC50 (μM) of in theELISA assay represents the concentration of compound at which 50% signalhas been inhibited.

IC50 (β-amyloid) IC50 (S100b) Example (μM) (μM) 1 0.85 0.66 2 0.76 0.553 0.80 0.84 4 0.65 0.54 5 1.02 0.71 6 0.78 0.77 7 1.17 1.05 8 1.26 0.809 1.59 1.13 10 1.32 1.14 11 1.02 0.81 12 1.19 0.98 13 2.16 4.61 14 2.374.56 15 2.47 3.14 16 1.55 3.13Pharmacokinetics

Pharmacokinetic screening in rats was performed on various compounds tomeasure brain and plasma concentrations at 6 hour time point.

The parameters for the pharmacokinetic protocol were as follows.

-   Amount of compound: 5 mg/kg-   Species: Rat; Strain: Sprague Dawley; Sex: Male-   Average body weight at dose: weight ranged from 271 to 423 grams-   Average age at dose: age ranged from 9 to 14 weeks-   Diet Status: Overnight fasting-   Number of Animals (n) for each time point: 2-   Dosing: Oral (PO)-   Formulation: 2% Tween 80 in distilled water

Each formulation was administered once by oral gavage. The dose volumewas 5 mL/kg for all animals. The actual volume administered to eachanimal was calculated and adjusted based on the most recent body weight.

Blood samples (approximately 300 μL whole blood) at (1, 2, and 4 h) wascollected from each animal via tail vein except for terminal bloodsamples. Terminal blood (6 h) samples were collected via cardiacpuncture. All samples were collected into tubes containing lithiumheparin (Multivette 600 LH-Gel, Sarstedt, Newton, N.C., USA). Followingcollection, the tubes were placed in refrigerator (maximum 30 minutes)or until centrifugation under refrigeration (at 2 to 8° C.) at 1500 gfor approximately 15 minutes. Each harvested plasma sample was thentransferred into 1.2 mL polypropylene tubes, on the 96-Well Plateaccording to the 96-Well Plate plasma sample map and kept in freezer.Plasma samples were then analyzed for test substances.

Brain samples were collected immediately after the animals wereeuthanized at designated time points. Brain samples were rinsed withsaline, blotted dry, and weighed. Brain samples were placed intoindividual containers and kept in freezer (−20° C.). Brain samples werethen analyzed for test articles.

After analysis, all the plasma results are reported as ng/mL and brainsample results are reported as ng/g. In the table below, “ND” stands fornot determined and “NA” stands for not applicable.

Brain Plasma B/P Ex. (ng/g) (ng/mL) Ratio R¹ R² Q¹ Config Z 697 92 7.7—CH₃CH₂ —CH₃CH₂ butyl NA 1 626 18 34.1 —CH₃ —CH₃ butyl R 2 718 24 30.6—CH₃CH₂ —CH₃CH₂ butyl R 3 1120 48 23.3 —CH₃ —CH₃ butyl S 4 610 74 8.8—CH₃CH₂ —CH₃CH₂ butyl S 5 3325 200 16.7 —CH₃ —CH₃ ethoxymethyl R 6 3905155 25.3 —CH₃ —CH₃ ethoxymethyl S 7 1385 153 9.1 —CH₃CH₂ —CH₃ethoxymethyl R 8 2705 137 19.6 —CH₃CH₂ —CH₃ ethoxymethyl S 9 537 76 7.2H —CH₃ butyl R 10 212 74 2.9 H —CH₃ butyl S 11 343 72 4.8 H —CH₃CH₂butyl R 12 540 124 4.5 H —CH₃CH₂ butyl S 13 ND ND ND H —CH₃ ethoxymethylR 14 ND ND ND H —CH₃ ethoxymethyl S 15 ND ND ND H —CH₃CH₂ ethoxymethyl R16 ND ND ND H —CH₃CH₂ ethoxymethyl S

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forRAGE-mediated disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

We claim:
 1. A compound of Formula (X)

wherein Q¹ is selected from the group consisting of —CH₂OCH₂CH₃ and—CH₂CH₂CH₂CH₃. 2.4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol. 3.A pharmaceutical composition comprising4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol anda pharmaceutically acceptable carrier.